The Matrix Biochemistry Section focuses its research on the functions of five disordered noncollagenous proteins first found associated with the mineralized matrix of bones and teeth but that we have shown are also made by many metabolically active ductal epithelial cells. The five proteins are bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein-1 (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE). We have made a strong case for the genetic relatedness of these seemingly different proteins and there is increasing acceptance of the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family concept. The genes encoding these proteins are all clustered in a tandem fashion within a short (400,000 base pairs) region of human chromosome 4 and similarly on all other mammals studied to date. After comparing the intron-exon structures and conserved motifs of their respective protein-encoding exons, we proposed that the five genes might be the result of ancient gene duplication and subsequent divergence. The most recent event appears to be a duplication of the DMP1 gene in the common ancestor of mammals and reptiles. Both lines then independently modified a different DMP1 gene to become DSPP-like during the evolution of modern dentin. We and others have shown that all known cases of non-syndromic Dentin Dysplasia (DD) and Dentinogenesis Imperfecta (DGI) are the result of either a variety of point mutations at the very beginning of the DSPP gene or deletions later in the gene that result in frameshift mutations within the long repeat domain. In the past we proposed that all known mutations have dominant negative effects (mutations in a single copy of the gene cause the diseases but complete loss of one copy does not) but the mechanisms for this remained unexplored. We have shown that all known mutations (except Y6D) cause the retention of the mutant DSPP proteins in the endoplasmic reticulum of our model system. Furthermore, we have shown that the retained mutant proteins cause the loss in the DSPP protein made from the normal allele. Mutations resulting in only small amounts of the normal DSPP protein being secreted out of the cells cause the more severe disease, DGI. Our current research involves a focus on the trafficking of proteins that tend to form inappropriate aggregates while transiting through the endoplasmic reticulum (ER) as well as how the cells naturally destroy disordered proteins that fail to traffic out of the ER. Searching databases, we have found that many secreted proteins encode similar peptide motifs that we propose are used to interact with a conserved ER cargo receptor. This proposed cargo receptor then traffics negatively charged proteins (as well as a variety of other proteins that have tendencies to either self-aggregate or form complexes with co-translated proteins) out of the ER before they can reach high enough concentrations to form aggregates and cause cells to malfunction.